Diabetes mellitus is a serious illness that affects an increasing number of people across the world. A recent press release by the International Diabetes Federation suggests that by 2025, there will be a total of 380 million people worldwide suffering from diabetes [http://www.idf.org/home/index.cfm?unode=E86A829B-F6FE-44FB-95EA-C3A71439F2B7]. The incidence of diabetes in many countries is escalating in parallel with an upward trend in obesity. Serious consequences of diabetes include increased risk of stroke, heart disease, kidney damage, blindness, and amputation. Cardiovascular diseases are the cause of death of more than 70% of patients with Type 2 diabetes mellitus (T2DM) [B. Pourcet et al. Expert Opin. Emerging Drugs 2006, 11, 379-401.]
Diabetes is characterized by decreased insulin secretion and/or an impaired ability of peripheral tissues to respond to insulin, resulting in increased plasma glucose levels. There are two forms of diabetes: insulin-dependent and non-insulin-dependent, with the great majority of diabetics suffering from the non-insulin-dependent form of the disease, known as type 2 diabetes or non-insulin-dependant diabetes mellitus (NIDDM). Because of the serious consequences, there is an urgent need to control diabetes.
The metabolic syndrome is a condition where patients exhibit more than two of the following symptoms: obesity, hypertriglyceridemia, low levels of HDL-cholesterol, high blood pressure, and elevated fasting glucose levels [R. H. Eckel Proc. Nutr. Soc. 2007, 66, 82-95; J.-P. Després and I. Lemieux Nature 2006, 444, 881-887; E. Ratto et al. J. Am Soc. Nephrol. 2006, 17, S120-S122; A. M. McNeill et al. Diabetes Care 2005, 28, 385-390]. This syndrome is often a precursor of type 2 diabetes, and has high prevalence in the United States, estimated at 24% [E. S. Ford et al. JAMA 2002, 287, 356]. A therapeutic agent that ameliorates the metabolic syndrome would be useful in potentially slowing or stopping the progression to type 2 diabetes.
A number of tests are used to assess diabetic patients. Fasting blood glucose levels and glucose tolerance tests are used to measure directly the amount of glucose in the blood and the ability of the body to respond to a glucose challenge. However, the level of variability of blood glucose levels is relatively high, particularly in diabetic patients, and so alternative tests are also used. One of the most common alternatives is the HbA1c test, which tests for the levels of glycosylated hemoglobin in the red blood cells [D. R. McCane et al. BMJ 1994, 308, 1323-1328; R. J. McCarter et al. Diabetes Care 2006, 29, 352-355]. Red blood cells have a normal life-span of 120 days in the body, and they contain hemoglobin which becomes progressively glycosylated, with the level of glycosylation correlating with the average levels of blood glucose. As a result, the HbA1c levels give an indication of the average levels of blood glucose over the preceding 3-4 months, and they do not fluctuate during the course of the day. The level of HbA1c in normal blood is approximately 5%, and the level in poorly controlled diabetic patients is 8% or above. The current guideline from the American Diabetes Association is to maintain the HbA1c level below 7%. This level corresponds to a mean plasma glucose level of approximately 170 mg/dL [D. E. Goldstein et al. Diabetes Care 2004, 27, 1761-1773].
Treatment of NIDDM generally starts with weight loss, a healthy diet and an exercise program. These factors are especially important in addressing the increased cardiovascular risks associated with diabetes, but they are generally ineffective in controlling the disease itself. There are a number of drug treatments available, including insulin, metformin, sulfonylureas, acarbose, thiazolidinediones, GLP-1 analogues, and DPP IV inhibitors. However, several of these treatments have disadvantages, and there is an ongoing need for new drugs to treat diabetes.
For example, metformin is an effective agent that reduces fasting plasma glucose levels and enhances the insulin sensitivity of peripheral tissue. Metformin has a number of effects in vivo, including an increase in the synthesis of glycogen, the polymeric form in which glucose is stored [R. A. De Fronzo Drugs 1999, 58 Suppl. 1, 29]. Metformin also has beneficial effects on lipid profile, with favorable results on cardiovascular health. Treatment with metformin leads to reductions in the levels of LDL cholesterol and triglycerides [S. E. Inzucchi JAMA 2002, 287, 360]. However, over a period of years, metformin loses its effectiveness [R. C. Turner et al. JAMA 1999, 281, 2005] and there is consequently a need for new treatments for diabetes.
Thiazolidinediones are activators of the nuclear receptor peroxisome-proliferator activated receptor-gamma (PPARγ). They are effective in reducing blood glucose levels, and their efficacy has been attributed primarily to decreasing insulin resistance in skeletal muscle [M. Tadayyon and S. A. Smith Expert Opin. Investig. Drugs 2003, 12, 307]. Three thiazolidinediones have been approved for use in the United States for the treatment of diabetes but one was subsequently withdrawn because of hepatotoxicity issues. The two currently approved drugs, pioglitazone and rosiglitazone, are effective in reducing blood sugar and HbA1c levels in diabetic patients [G. Boden and M. Zhang Expert Opin. Investig. Drugs 2006, 15, 243-250; B. Pourcet et al. Expert Opin. Emerging Drugs 2006, 11, 379-401]. However, a period of 3-4 months is required before full efficacy is seen [G. Boden and M. Zhang Op. Cit.], and one disadvantage associated with the use of thiazolidinediones is weight gain.
Sulfonylureas bind to the sulfonylurea receptor on pancreatic beta cells, stimulate insulin secretion, and consequently reduce blood glucose levels. Weight gain is also associated with the use of sulfonylureas [S. E. Inzucchi JAMA 2002, 287, 360] and, like metformin, they lose efficacy over time [R. C. Turner et al. JAMA 1999, 281, 2005]. A further problem often encountered in patients treated with sulfonylureas is hypoglycemia [M. Salas J. J. and Caro Adv. Drug React. Tox. Rev. 2002, 21, 205-217].
Acarbose is an inhibitor of the enzyme alpha-glucosidase, which breaks down disaccharides and complex carbohydrates in the intestine. It has lower efficacy than metformin or the sulfonylureas, and it causes intestinal discomfort and diarrhea which often lead to the discontinuation of its use [S. E. Inzucchi JAMA 2002, 287, 360]
Although drugs have been approved for the treatment of diabetes using a number of different mechanisms, and many other drugs are being evaluated clinically, there remains a need to invent new compounds for the treatment of diabetes. It has recently been disclosed that the results of the United Kingdom Prospective Study indicate that over time, a decline is seen in the beta cell function of diabetic patients irrespective of whether they were being treated with diet, sulfonylureas, metformin, or insulin [R. R. Holman Metabolism 2006, 55, S2-S5].
One possible target for the treatment of diabetes which has received much attention recently is 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) [see for example M. Wang Curr. Opin. Invest. Drugs 2006, 7, 319-323]. 11β-HSD1 is an enzyme that catalyzes the reduction of cortisone to cortisol (or dehydrocorticosterone to corticosterone in rodents). Cortisol is a corticosteroid hormone produced in the adrenal gland, and it has been shown to increase levels of glucose production, mostly by increasing gluconeogenesis [S. Khani and J. A. Tayek Clinical Sci. 2001, 101, 739-747]. A second enzyme, 11β-hydroxysteroid dehydrogenase type II (11β-HSD2) is responsible for the oxidation of cortisol to cortisone. The enzymes have low homology and are expressed in different tissues. 11β-HSD1 is highly expressed in a number of tissues including liver, adipose tissue, and brain, while 11β-HSD2 is highly expressed in mineralocorticoid target tissues, such as kidney and colon. 11β-HSD2 prevents the binding of cortisol to the mineralocorticoid receptor, and defects in this enzyme have been found to be associated with the syndrome of apparent mineralocorticoid excess (AME).
There is evidence from transgenic mice, and also from small clinical studies in humans, that confirm the therapeutic potential of the inhibition of 11β-HSD1 for the treatment of Type 2 Diabetes mellitus.
Experiments with transgenic mice indicate that modulation of the activity of 11β-HSD1 could have beneficial therapeutic effects in diabetes and in the metabolic syndrome. For example, when the 11β-HSD1 gene is knocked out in mice, fasting does not lead to the normal increase in levels of G6Pase and PEPCK, and the animals are not susceptible to stress- or obesity-related hyperglycemia. Moreover, knockout animals which are rendered obese on a high-fat diet have significantly lower fasting glucose levels than weight-matched controls (Y. Kotolevtsev et al. Proc. Natl. Acad. Sci. USA 1997, 94, 14924). 11β-HSD1 knockout mice have also been found to have improved lipid profile, insulin sensitivity, and glucose tolerance (N. M. Morton et al. J. Biol. Chem. 2001, 276, 41293). The effect of overexpressing the 11β-HSD1 gene in mice has also been studied. These transgenic mice displayed increased 11β-HSD1 activity in adipose tissue, and they also exhibit visceral obesity which is associated with the metabolic syndrome. Levels of the corticosterone were increased in adipose tissue, but not in serum, and the mice had increased levels of obesity, especially when on a high-fat diet. Mice fed on low-fat diets were hyperglycemic and hyperinsulinemic, and also showed glucose intolerance and insulin resistance (H. Masuzaki et al. Science, 2001, 294, 2166).
The effects of the non-selective 11β-hydroxysteroid dehydrogenase inhibitor carbenoxolone have been studied in a number of small trials in humans. In one study, carbenoxolone was found to lead to an increase in whole body insulin sensitivity, and this increase was attributed to a decrease in hepatic glucose production (B. R. Walker et al. J. Clin. Endocrinol. Metab. 1995, 80, 3155). In another study, decreased glucose production and glycogenolysis in response to glucagon challenge were observed in diabetic but not healthy subjects (R. C. Andrews et al. J. Clin. Enocrinol. Metab. 2003, 88, 285). Finally, carbenoxolone was found to improve cognitive function in healthy elderly men and also in type 2 diabetics (T. C. Sandeep et al. Proc. Natl. Acad. Sci USA 2004, 101, 6734).
A number of non-specific inhibitors of 11β-HSD 1 and 11I -HSD2 have been identified, including glycyrrhetinic acid, abietic acid, and carbenoxolone. In addition, a number of selective inhibitors of 11β-HSD 1 have been found, including chenodeoxycholic acid, flavanone and 2′-hydroxyflavanone (S. Diederich et al. Eur. J. Endocrinol. 2000, 142, 200 and R. A. S. Schweizer et al. Mol. Cell. Endocrinol. 2003, 212, 41).
A need exists in the art, therefore, for 11β-HSD1 inhibitors that have efficacy for the treatment of diseases such as, for example, type II diabetes mellitus and metabolic syndrome. Further, a need exists in the art for 11β-HSD1 inhibitors having IC50 values less than about 1 μM.